Cell Plasticity and its role in the propagation of drug tolerant states

Throughout neoplastic evolution, cancer cells are subjected to fast-paced environmental changes that drive micro-evolutionary processes giving rise to different sub-clones within the population. This heterogeneity may arise either as a result of the accumulation of somatic mutations or due to the ability of the same genotype to produce many discrete – sometimes dramatically different – phenotypes in response to the variable nature of the microenvironment. The latter phenomenon, termed phenotypic plasticity, represents an undeniable source of phenotypic diversity underlying the rapid adaptation of a cellular system to environmental cues. Interestingly, our data suggests that phenotypic plasticity may play a key role in the rapid adaptation of cancer cells to cytotoxic antitumoral agents. Indeed, our results indicate that clonal populations of cancer cells display fractional killing upon exposure to TRAIL (TNF Related Apoptosis Factor Induced Ligand) and show that TRAIL-survivors acquire and maintain a drug-tolerant state upon continuous exposure to this ligand. Interestingly, when TRAIL treatment is discontinued, cells lose the “drug-tolerant state” following several cell divisions and revert to the initial response observed in naïve populations. This phenomenon of reversible resistance suggests that the TRAIL-tolerant state is maintained in a TRAIL-dependent manner and it is not due to the selection of inherently resistant clones present within the naive population. Following our initial observations, the main goal of our work is to unravel the molecular mechanisms that orchestrate the establishment, maintenance and temporal propagation of stable phenotypic states within isogenic populations of cancer cells when challenged with a cytotoxic agent. We hypothesize that individual cells within an isogenic population display variable gene expression/epigenetic profiles determining conserved phenotypic lineages which may vary significantly in their response to environmental cues. In that regard, we propose that lineage switching – the ability of a cell to change its molecular properties and convert to a different stable phenotype – lies at the basis of non-genetic adaptation. Overall, our research will shed light onto the molecular basis orchestrating the acquisition of “temporal molecular memory” underlying the inheritance of complex and reversible epigenetic traits.